Antiviral Compounds Discovered by Virtual Screening of Small−Molecule Libraries against Dengue Virus E Protein

• DOI: 10.1021/cb800176t
• Publication Date: 2008-11-24T21:35:47Z
• Authors: Zhigang Zhou; Mansoora Khaliq; Jae-Eun Suk; Chinmay Patkar; Long Li; Richard J. Kuhn; Carol Beth Post
• Keywords: Viral protein; Flavivirus; Docking (animal)

Infection by the mosquito-borne dengue virus causes fever and sometimes fatal hemorrhagic fever. The increasing number of infections per year suggests that is becoming more virulent its transmission expanding. Nevertheless, no effective treatment for infection currently exists. In a search antiviral agents against virus, we investigated potential targeting structural protein site rather than an enzymatic one. Using this approach, now report discovery small molecule ligand inhibits viral growth. Our results also provide first evidence binding site, pocket located at hinge between domains 1 2 envelope (E protein) on surface, valid target therapy. Ligand candidates were identified from libraries ∼142,000 compounds using computational high-throughput screening protocol E protein. Cell-based assays conducted 23 top-ranked compounds. Among four with good activity profiles, compound P02 was found to inhibit reproduction micromolar concentrations. saturation transfer difference NMR spectroscopy, show binds competes known N-octyl-β-d-glucoside. Together, are consistent inhibition mechanism maturation or host-cell entry mediated E-protein pocket. promising lead future development related flaviviruses.